Theophylline and theobromine derivatives

ABSTRACT

A novel compound has the following formula: ##STR1## in which R 1  and R 2  are methyl or a group having the formula: ##STR2## provided that one of R 1  and R 2  is methyl and the other is said group, wherein R stands for a hydrogen atom or a lower alkyl group, Z stands for a group ##STR3## in which X 1  and X 2 , which may be the same or different, stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, or a pyridyl group or a group ##STR4## in which Y 1  and Y 2 , which may be the same or different stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, X stands for a nitrogen or carbon atom, and n is an integer of from 2 to 10, provided that when R 2  is the group having the formula II, X is not carbon and Z is not pyridyl.

This is a division of application Ser. No. 298,227, filed Aug. 31, 1981, now U.S. Pat. No. 4,426,383.

The present invention relates to a theophylline derivative and a theobromine derivative and then processes for manufacturing them. These compounds are novel and have excellent medicinal actions.

More particularly, the theophylline and theobromine derivatives have the following formula. ##STR5## in which R₁ and R₂ are methyl or a group having the formula: ##STR6## provided that one of R₁ and R₂ is methyl and the other is said group, wherein R stands for a hydrogen atom or a lower alkyl group, Z stands for a group ##STR7## in which X₁ and X₂, which may be the same or different, stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, or a pyridyl group or a group ##STR8## in which Y₁ and Y₂, which may be the same or different stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, X stands for a nitrogen or carbon atom, and n is an integer of from 2 to 10, provided that when R₂ is the group having the formula II, X is not carbon and Z is not pyridyl.

The invention includes an acid addition salt of the derivatives defined as above as well.

Among the compounds according to the invention, the theophylline derivatives have the following formula III. ##STR9## wherein R stand for a hydrogen atom or a lower alkyl group, Z stands for a group ##STR10## in which X₁ and X₂, which may be the same or different, stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, or a pyridyl group or a group ##STR11## in which Y₁ and Y₂, which may be the same or different stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, X stands for a nitrogen or carbon atom, and n is an integer of from 2 to 10.

Then, the theobromine derivatives have the following formula IV. ##STR12## wherein R stands for a hydrogen atom or a lower alkyl group, Z stands for a group ##STR13## in which X₁ and X₂, which may be the same or different, stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, or a group ##STR14## in which Y₁ and Y₂, which may be the same or different, stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a halogen atom, and n is an integer of from 2 to 10.

In the definitions of R, X₁, X₂, Y₁ and Y₂ of the general formula [I], by the term "lower alkyl group" are meant linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl groups. By the term "lower alkoxy group" are meant alkoxy groups corresponding to the above-mentioned lower alkyl groups. As the halogen atom, there can be mentioned chlorine, bromine, iodine and fluorine.

Among theobromine derivatives defined as before, those having the formula IV in which Z is ##STR15## or Z is ##STR16## and n is 2,9 or 10 is preferable.

The compound [I] of the present invention can easily be converted to an acid addition salt by reaction with a pharmacologically acceptable inorganic or organic acid. As the inorganic acid, there can be mentioned hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, and as the organic acid, there can be mentioned maleic acid, fumaric acid, succinic acid, acetic acid, malonic acid, citric acid and benzoic acid.

Typical examples of the theophilline derivatives of the invention will now be mentioned, though the scope of the present invention is not limited by these examples.

7-{2-[4-p-chlorobenzhydrylpiperazinyl-(1)]ethyl}-theophylline

7-{3-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-propyl}-theophylline

7-{4-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-p-methylbenzhydrylpiperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[4-p-methoxybenzhydrylpiperazinyl-(1)]-n-hexyl}-theophylline

7-{7-[4-o-trifluoromethylbenzhydrylpiperazinyl-(1)]-n-heptyl}-theophylline

7-{8-[4-benzhydrylpiperazinyl-(1)]-n-octyl}-theophylline

7-{9-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-nonyl}-theophylline

7-{10-[4-p-ethoxybenzhydrylpiperazinyl-(1)]-n-decyl}-theophylline

7-{4-[4-(4',4"-dichlorodiphenylmethyl)piperazinyl-(1)]-n-butyl}-theophylline

7-{2-[(4-phenyl)piperazinyl-(1)]ethyl}-theophylline

7-{3-[(4-phenyl)piperazinyl-(1)]-n-propyl}-theophylline

7-{4-[(4-phenyl)piperazinyl-(1)]-n-butyl}-theophylline

7-{5-[(4-phenyl)piperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[(4-phenyl)piperazinyl-(1)]-n-hexyl}-theophylline

7-{2-[4-o-methylphenylpiperazinyl-(1)]-ethyl}-theophylline

7-{3-[4-o-methylphenylpiperazinyl-(1)]-n-propyl}-theophylline

7-{5-[4-o-methylphenylpiperazinyl-(1)]-n-pentyl}-theophylline

7-{2-[4-m-methylphenylpiperazinyl-(1)]-ethyl}-theophylline

7-{4-[4-m-methylphenylpiperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-m-methylphenylpiperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[4-m-methylphenylpiperazinyl-(1)]-n-hexyl}-theophylline

7-{2-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-ethyl}-theophylline

7-{2-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-ethyl}-theophylline

7-{2-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theophylline

7-{4-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-hexyl}-theophylline

7-{3-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theophylline

7-{4-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-hexyl}-theophylline

7-{2-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-ethyl}-theophylline

7-{3-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theophylline

7-{4-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-hexyl}-theophylline

7-{2-[4-o-methoxyphenylpiperazinyl-(1)]-ethyl}-theophylline

7-{3-[4-o-methoxyphenylpiperazinyl-(1)]-n-propyl}-theophylline

7-{4-[4-o-methoxyphenylpiperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-o-methoxyphenylpiperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[4-o-methoxyphenylpiperazinyl-(1)]-n-hexyl}-theophylline

7-{2-[4-m-methoxyphenylpiperazinyl-(1)]-ethyl}-theophylline

7-{3-[4-m-methoxyphenylpiperazinyl-(1)]-n-propyl}-theophylline

7-{4-[4-m-methoxyphenylpiperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-m-methoxyphenylpiperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[4-m-methoxyphenylpiperazinyl-(1)]-n-hexyl}-theophylline

7-{2-[4-p-methoxyphenylpiperazinyl-(1)]-ethyl}-theophylline

7-{4-[4-p-methoxyphenylpiperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-p-methoxyphenylpiperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[4-p-methoxyphenylpiperazinyl-(1)]-n-hexyl}-theophylline

7-{2-[4-o-chlorophenylpiperazinyl-(1)]-ethyl}-theophylline

7-{4-[4-o-chlorophenylpiperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-o-chlorophenylpiperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[4-o-chlorophenylpiperazinyl-(1)]-n-hexyl}-theophylline

7-{2-[4-m-chlorophenylpiperazinyl-(1)]-ethyl}-theophylline

7-{4-[4-m-chlorophenylpiperazinyl-(1)]-n-butyl}-theophylline

7-{4-[4-m-chlorophenylpiperazinyl-(1)]-n-pentyl}-theophylline

7-{2-[4-o-chlorophenylpiperazinyl-(1)]-ethyl}-theophylline

7-{4-[4-o-chlorophenylpiperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-o-chlorophenylpiperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[4-o-chlorophenylpiperazinyl-(1)]-n-hexyl}-theophylline

7-{2-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-ethyl}-theophylline

7-{3-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-propyl}-theophylline

7-{4-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-butyl}-theophylline

7-{4-[4-p-fluorophenylpiperazinyl-(1)]-n-propyl}-theophylline

7-{5-[4-p-fluorophenylpiperazinyl-(1)]-n-butyl}-theophylline

7-{3-[4-m-trifluoromethylphenylpiperazinyl-(1)]-n-propyl}-theophylline

7-{4-[4-m-trifluoromethylphenylpiperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-m-trifluoromethylphenylpiperazinyl-(1)]-n-pentyl}-theophylline

7-{4-[4-o-trifluoromethylphenylpiperazinyl-(1)]-n-butyl}-theophylline

7-{3-[4-p-trifluoromethylphenylpiperazinyl-(1)]-n-propyl}-theophylline

7-{2-[4-(2-pyridyl)piperazinyl-(1)]-ethyl}-theophylline

7-{3-[4-(2-pyridyl)piperazinyl-(1)]-n-propyl}-theophylline

7-{4-[4-(2-pyridyl)piperazinyl-(1)]-n-butyl}-theophylline

7-{5-[4-(2-pyridyl)piperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[4-(2-pyridyl)piperazinyl-(1)]-n-hexyl}-theophylline

7-{7-[(3-methyl-4-m-methylphenyl)piperazinyl-(1)]-n-heptyl}-theophylline

7-{2-[(3-methyl-4-phenyl)piperazinyl-(1)]-ethyl}-theophylline

7-{4-[(3-methyl-4-phenyl)piperazinyl-(1)]-n-butyl}-theophylline

7-{5-[(3-methyl-4-phenyl)piperazinyl-(1)]-n-pentyl}-theophylline

7-{2-[(3-methyl-4-p-methoxyphenyl)piperazinyl-(1)]-ethyl}-theophylline

7-{5-[(3-methyl-4-p-methoxyphenyl)piperazinyl-(1)]-n-pentyl}-theophylline

7-{6-[(3-ethyl-4-p-methoxyphenyl)piperazinyl-(1)]-n-hexyl-theophylline

7-{7-[4-m-chlorophenylpiperazinyl-(1)]-n-heptyl}-theophylline

7-{8-[4-(3,4-dimethylphenyl)piperazinyl-(1)]-n-octyl}-theophylline

7-{9-[4-(2,3-diethylphenyl)piperazinyl-(1)]-n-nonyl}-theophylline

7-{10-[4-m-ethoxyphenylpiperazinyl-(1)]-n-decyl}-theophylline

7-{7-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-heptyl}-theophylline

7-{7-[4-(2-methyl-3-ethylphenyl)piperazinyl-(1)]-n-heptyl}-theophylline

7-{3-[4-(2-methyl-3-n-propylphenyl)piperazinyl-(1)]-n-propyl}-theophylline

7-{2-[(4-phenyl)piperidinyl]-ethyl}-theophylline

7-{3-[(4-phenyl)piperidinyl]-n-propyl}-theophylline

7-{4-[(4-phenyl)piperidinyl]-n-butyl}-theophylline

7-{5-[(4-p-chlorophenyl)piperidinyl]-n-pentyl}-theophylline

7-{5-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-pentyl}-theophylline

7-{7-[4-(2-methyl-5-chlorophenyl)piperazinyl-(1)]-n-heptyl}-theophylline

7-{1-[(4-o-methoxyphenyl)piperazinyl-(1)]-n-decyl}-theophylline

7-{10-[4-(2-methyl-5-chlorophenyl)piperazinyl-(1)]-n-decyl}-theophylline

7-{10-[3-methyl-4-m-methylphenylpiperazinyl-(1)]-n-decyl}-theophylline

7-{10-[4-(3,4-dimethylphenyl)piperazinyl-(1)]-n-decyl}-theophylline

Theophylline derivatives provided according to the present invention are novel compounds which have not been introduced in any of literature references. They have very high vasolidating and blood flow-increasing actions and they are effective for improving blood flows in the cerebral and coronary arteries and the capillary vessels. Furthermore, the compounds of the present invention have an action of controlling coagulation of blood platelets. Accordingly, they are suitable as agents for remedy of various diseases caused by troubles in blood flows in capillary vessels, cerebral blood vessel disorders and sequelae thereof, stenocardia and cardiac infraction. Moreover, theophylline derivatives provided according to the present invention are excellent in other various pharmacological actions such as the action to the central nervous system, the anti-histaminic action, the analgesic action, the anti-asthmatic action and the hypotensive action. Accordingly, the compounds of the present invention can effectively be used as psychic energizers, anti-histaminic agents, analgesic agents, anti-asthmatic agents and hypotensive agents.

Compounds [III] of the present invention can be prepared according to various processes. For example, a process represented by the following reaction formula is ordinarily adopted: ##STR17## wherein A stands for a halogen atom or a p-toluene-sulfonyloxy group, and R, X, Z and n are as defined above.

In short, a compound III of the present invention can be obtained by reacting a compound represented by the general formula V with a compound represented by the general formula VI.

This reaction is carried out in the absence of a solvent or in the presence of a solvent not participating in the reaction, which is appropriately selected from lower alcohols such as methanol, ethanol, propanol and isopropanol, benzene type solvents such as benzene, toluene and xylene, and ethers such as ethyl ether and tetrahydrofuran. The reaction can be advanced even at room temperature, but it is preferred that the reaction be carried out at an elevated temperature of up to the boiling point of the solvent. The reaction can be performed more smoothly by adding an acid binder such as triethylamine, an alkali metal bicarbonate, an alkali metal carbonate or pyridine to the reaction mixture.

Typical examples of the theobromine derivatives of the invention will now be mentioned, though the scope of the present invention is not limited by these examples.

1-{7-[4-o-methoxyphenylpiperazinyl-(1)]-n-heptyl}-theobromine

1-{6-[4-o-methoxyphenylpiperazinyl-(1)]-n-hexyl}-theobromine

1-{5-[4-m-methoxyphenylpiperazinyl-(1)]-n-pentyl}-theobromine

1-{6-[4-m-methoxyphenylpiperazinyl-(1)]-n-hexyl}-theobromine

1-{8-[4-o-methoxyphenylpiperazinyl-(1)]-n-octyl}-theobromine

1-{10-[4-m-methoxyphenylpiperazinyl-(1)]-n-decyl}-theobromine

1-{2-[4-p-methoxyphenylpiperazinyl-(1)]-ethyl}-theobromine

1-{4-[4-o-ethoxyphenylpiperazinyl-(1)]-n-butyl}-theobromine

1-{4-[4-o,m-dimethylphenylpiperazinyl-(1)]-n-butyl}-theobromine

1-{2-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-ethyl}-theobromine

1-{3-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theobromine

1-{4-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theobromine

1-{5-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theobromine

1-{2-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-ethyl}-theobromine

1-{3-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theobromine

1-{4-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theobromine

1-{5-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theobromine

1-{6-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-hexyl}-theobromine

1-{2-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-ethyl}-theobromine

1-{3-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-propyl}-theobromine

1-{4-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-butyl}-theobromine

1-{5-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-pentyl}-theobromine

1-{6-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-hexyl}-theobromine

1-{7-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-heptyl}-theobromine

1-{8-[4-(2,3-dimethylphenyl)piperazinyl-(1)]-n-octyl}-theobromine

1-{9-[4-(2,6-dimethylphenyl)piperazinyl-(1)]-n-nonyl}-theobromine

1-{10-[4-(2,5-dimethylphenyl)piperazinyl-(1)]-n-decyl}-theobromine

1-{5-[4-benzhydrylpiperazinyl-(1)]-n-pentyl-theobromine

1-{2-[4-benzhydrylpiperazinyl-(1)]-ethyl}-theobromine

1-{3-[4-benzhydrylpiperazinyl-(1)]-n-propyl}-theobromine

1-{4-[4-benzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine

1-{5-[4-benzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine

1-{6-[4-benzhydrylpiperazinyl-(1)]-n-hexyl}-theobromine

1-{2-[4-p-chlorobenzhydrylpiperazinyl-(1)]-ethyl}-theobromine

1-{3-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-propyl}-theobromine

1-{4-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-butyl}-theobromine

1-{5-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine

1-{6-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-hexyl}-theobromine

1-{10-[4-p-methoxybenzhydrylpiperazinyl-(1)]-n-decyl}-theobromine

1-{4-[4-(4',4"-dichlorophenylmethyl)piperazinyl-(1)]-n-butyl}-theobromine

1-{9-[4-p-chlorobenzhydrylpiperazinyl-(1)]-n-nonyl}-theobromine

1-{8-[4-p-methylbenzhydrylpiperazinyl-(1)]-n-octyl}-theobromine

1-{7-[4-p-trifluoromethylbenzhydrylpiperazinyl-(1)]-n-heptyl}-theobromine

1-{6-[4-o-methylphenylpiperazinyl-(1)]-n-hexyl}-theobromine

1-{2-[4-m-methylphenylpiperazinyl-(1)]-ethyl}-theobromine

1-{3-[4-p-methylphenylpiperazinyl-(1)]-n-propyl}-theobromine

1-{4-[4-m-methylphenylpiperazinyl-(1)]-n-butyl}-theobromine

1-{5-[4-p-methylphenylpiperazinyl-(1)]-n-pentyl}-theobromine

1-{7-[4-p-trifluoromethylpiperazinyl-(1)]-n-heptyl}-theobromine

1-{8-[4-p-ethoxyphenylpiperazinyl-(1)]-n-octyl}-theobromine

1-{2-[4-o-chlorophenylpiperazinyl-(1)]-ethyl}-theobromine

1{3-[4-p-chlorophenylpiperazinyl-(1)]-n-propyl}-theobromine

1-{4-[4-o-chlorophenylpiperazinyl-(1)]-n-butyl}-theobromine

1-{5-[4-p-chlorophenylpiperazinyl-(1)]-n-pentyl}-theobromine

1-{6-[4-m-chlorophenylpiperazinyl-(1)]-n-hexyl}-theobromine

1-{7-[4-p-methoxyphenylpiperazinyl-(1)]-n-heptyl}-theobromine

1-{3-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-propyl}-theobromine

1-{4-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-butyl}-theobromine

1-{5-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-pentyl}-theobromine

1-{6-[4-(2,3-dichlorophenyl)piperazinyl-(1)]-n-hexyl}-theobromine

1-{7-[4-(2,5-dichlorophenyl)piperazinyl-(1)]-n-heptyl}-theobromine

1-{8-[4-(2,6-dichlorophenyl)piperazinyl-(1)]-n-octyl}-theobromine

1-{9-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-nonyl}-theobromine

1-{10-[4-(3,4-dichlorophenyl)piperazinyl-(1)]-n-decyl}-theobromine

1-{2-[3-methyl-4-phenylpiperazinyl-(1)]-ethyl}-theobromine

1-{3-[3-methyl-4-phenylpiperazinyl-(1)]-n-propyl}-theobromine

1-{4-[3-methyl-4-phenylpiperazinyl-(1)]-n-butyl}-theobromine

1-{5-[3-methyl-4-phenylpiperazinyl-(1)]-n-pentyl}-theobromine

1-{6-[3-methyl-4-phenylpiperazinyl-(1)]-n-hexyl}-theobromine

1-{2-[3-methyl-4-p-methoxyphenylpiperazinyl-(1)]-ethyl}-theobromine

1-{3-[3-methyl-4-p-methoxyphenylpiperazinyl-(1)]-n-propyl}-theobromine

1-{4-[3-methyl-4-o-methoxyphenylpiperazinyl-(1)]-n-butyl}-theobromine

1-{5-[3-methyl-4-m-methoxyphenylpiperazinyl-(1)]-n-pentyl}-theobromine

1-{7-[4-p-fluorophenylpiperazinyl-(1)]-n-heptyl}-theobromine

1-{10-[3-methyl-4-m-methoxyphenylpiperazinyl-(1)]-n-decyl}-theobromine

1-{10-[4-(2,4-dimethylphenylpiperazinyl-(1)]-n-decyl}-theobromine

Theobromine derivatives provided according to the present invention are novel compounds which have not been introduced in any of literature references. They have very high vasolidating and blood flow-increasing actions and they are effective for improving blood flows in the cerebral and coronary arteries and the capillary vessels. Furthermore, the compounds of the present invention have an action of controlling coagulation of blood platelets. Accordingly, they are suitable as agents for remedy of various diseases caused by troubles in blood flows in capillary vessels, cerebral blood vessel disorders and sequelae thereof, stenocardia and cardiac infraction. Moreover, theobromine derivatives provided according to the present invention are excellent in other various pharmacological actions such as the action to the central vervous system, the anti-histaminic action, the amalgesic action, the anti-asthmatic action and the hypotensive action. Accordingly, the compounds of the present invention can effectively be used as psychic energizers, anti-histaminic agents, analgesic agents, anti-asthmatic agents and hypotensive agents.

Compounds [IV] of the present invention can be prepared according to various processes. For example, a process represented by the following reaction formula is ordinarily adopted: ##STR18## wherein X stands for a halogen atom or a p-toluene-sulfonyloxy group, and R, Z and n are as defined above.

In short, a compond IV of the present invention can be obtained by reacting a compound represented by the general formula VII with a compound represented by the general formula VIII.

This reaction is carried out in the absence of a solvent or in the presence of a solvent not participating in the reaction, which is appropriately selected from lower alcohols such as methanol, ethanol, propanol and isopropanol, benzene type solvents such as benzene, toluene and xylene, and ethers such as ethyl ether and tetrahydrofuran. The reaction can be advanced even at room temperature, but it is preferred that the reaction be carried out at an elevated temperature of up to the boiling point of the solvent. The reaction can be performed more smoothly by adding an acid binder such as triethylamine, an alkali metal bicarbonate, an alkali metal carbonate or pyridine to the reaction mixture.

Excellent physiological actions of the theophylline compound according to the invention will now be described with reference to typical compounds.

Blood Flow-Increasing Action

1. Methods

Male and female mongrel dogs having a body weight of 8 to 20 Kg were used as test animals, and the blood flows in the vertebral and femoral arteries were measured. More specifically, probes of an electromagnetic flow meter (Model MF-27 supplied by Nippon Koden) were attached to one side vertebral artery and one side femoral artery of a dog anesthetized by diethyl barbital (240 mg/kg, hypodermic injection) and sodium pentobarbital (10 mg/Kg, intravenous injection), and the blood flows of both the arteries were simultaneously measured. The test compound was administered by artery puncture at a dose of 0.1, 1 or 10 μg per Kg of the body weight.

2. Results:

The obtained results are shown in Table 2.

The intensity of the increase of the blood flow referred to in Table 2 was determined by using papaverine as a reference sample. The intensity of the sample having a minimum effective dose of 0.1 microgram/kg was designated as A and the intensity of the sample having a minimum effective dose of 1.0 microgram/kg was designated as B. Samples having a minimum effective dose of 10 microgram/kg were divided into two groups, one having an intensity higher than that of papaverine, and the intensity of the former group was designated as C and the intensity of the latter group was designated as D. The intensity of the sample having no activity was designated as E. Data of the increase of the blood flow and the duration of action, obtained with respect to 10 cases by using paraverine, are shown in Table 1.

                  TABLE 1                                                          ______________________________________                                         Dose              Increase in                                                                               Duration of                                       (microgram/       Blood Flow Action                                            kg)               (mean ± SE)                                                                            (minutes)                                         ______________________________________                                         Vertebral                                                                               1             0.3 ± 0.2                                                                             0.08 ± 0.05                                Artery  10            11.3 ± 2.7                                                                             0.55 ± 0.07                                Femoral  1             0.4 ± 0.3                                                                             0.09 ± 0.06                                Artery  10            12.6 ± 2.7                                                                             0.54 ± 0.07                                ______________________________________                                    

                                      TABLE 2                                      __________________________________________________________________________                                                  Increase in                                                                          Duration                                                                            Dose                                                           Class of                                                                            Blood Flow                                                                           of Action                                                                           (microgram/            Compound                                Activity                                                                            (ml)  (minutes)                                                                           kg)                    __________________________________________________________________________      ##STR19##                      vertebral artery femoral                                                               A Aery                                                                              101  27                                                                              7.8 1.7                                                                             0.1 0.1                 ##STR20##                      vertebral artery femoral                                                               D Cery                                                                               2  16                                                                               0.7 0.7                                                                             10 10                   ##STR21##                      vertebral artery femoral                                                               A Aery                                                                               4  22                                                                               0.6 1.3                                                                             0.1 0.1                 ##STR22##                      vertebral artery femoral                                                               B Bery                                                                               4  30                                                                               0.5 1.0                                                                             1 1                    __________________________________________________________________________

The theobromine derivatives were also examined in the same manner as described before in connection with the theophylline derivatives. Results are shown in Tables 3 and 4. From the results shown in Table 4, it will readily be understood that the compounds of the theobromine type have a very excellent blood flow-increasing action.

                  TABLE 3                                                          ______________________________________                                                           Increase in                                                  Dose              Blood Flow Duration of                                       (microgram/       (mean ± SE)                                                                            Action                                            kg)               (ml)       (minutes)                                         ______________________________________                                         Vertebral                                                                               1             0.3 ± 0.2                                                                             0.08 ± 0.05                                Artery  10            11.3 ± 2.7                                                                             0.55 ± 0.07                                Femoral  1             0.4 ± 0.3                                                                             0.09 ± 0.06                                Artery  10            12.6 ± 2.7                                                                             0.54 ± 0.07                                ______________________________________                                    

                                      TABLE 4                                      __________________________________________________________________________                                                  Increase of                                                                          Duration                                                                            Dose                                                           Class of                                                                            flood flow                                                                           of Action                                                                           (microgram/            Compound                                Activity                                                                            (ml)  (minutes)                                                                           kg)                    __________________________________________________________________________      ##STR23##                      vertebral artery femoral                                                               C Cery                                                                              65.4 94.1                                                                            1.52 1.72                                                                            10 10                  ##STR24##                       vertebral artery femoral                                                              A Aery                                                                               18.7 0.69 0.76                                                                           0.1 0.1                 ##STR25##                      vertebral artery femoral                                                               B Bery                                                                               27.8 84.5                                                                           0.68 1.89                                                                           1 1                     ##STR26##                      vertebral artery femoral                                                               A Aery                                                                               15.4 107.9                                                                          1.39 2.16                                                                            0.1 0.1               __________________________________________________________________________

The present invention will now be described in detail with reference to the following Examples that by no means limit the scope of the present invention.

EXAMPLE 1 Synthesis of 7-{2-[4-p-chlorobenzhydrylpiperazinyl-(1)-ethyl}-theopylline hydrochloride

In benzene, 6.3 g of 7-(2-bromoethyl)theophylline, 5.7 g of 1-(p-chlorobenzhydryl)piperazine and 4.0 g of triethylamine are stirred under reflux for 18.5 hours. Triethylamine hydrochloride is removed by filtration and the filtrate is extracted with dilute hydrochloric acid. The extract is made alkaline by dilute sodium hydroxide and is then extracted with chloroform. The chloroform layer is washed with water and dried with anhydrous potassium carbonate. The solvent is removed by distillation and the residual crude crystal is converted to a hydrochloride according to customary procedures. The hydrochloride is recrystallized from methyl cellosolve and water to obtain 4.8 g of intended 7-{2-[4-p-chlorobenzhydrylpiperazinyl-(1)]-ethyl}-theophylline hydrochloride (the yield being 42.5%).

Melting point: 250°-252° C.

Elementary Analysis Values as C₂₆ H₂₉ O₂ N₆ CH.2HCl: Calculated: C=55.16%, H=5.53%, N=14.85%. Found: C=55.19%, H=5.38%, N=14.87%.

EXAMPLE 2 Synthesis of 7-{4-[4-o-methoxyphenylpiperazinyl-(1)]-n-butyl}-thoephylline

In benzene, 6.9 g of 7-(4-bromo-n-butyl)theophylline, 3.8 g of o-methoxyphenylpiperazine and 4.0 g of triethylamine are stirred under reflux for 18 hours. The subsequent treatments are carried out in the same manner as described in Example 1. The obtained crude crystal is recrystallized from ethanol to obtain 3.8 g of intended 7-{4-[4-o-methoxyphenylpiperzinyl-(1)]n-butyl}-theophylline (the yield being 37.6%).

Melting Point: 117°-118° C.

Elementary Analysis Values as C₂₂ H₃₀ O₃ N₆ : Calculated: C=61.94%, H=7.10%, N=19.71%. Found: C=62.10%, H=7.21%, N=19.86%.

EXAMPLE 3 Synthesis of 7-{5-[4-o,m-dimethylphenylpiperazinyl-(1)-n-heptyl}-theophylline

In toluene, 9.9 g of 1-(5-bromo-n-heptyl)theophylline, 3.8 g of o,m-dimethylphenylpiperazine and 4.0 g of triethylamine are stirred under reflux for 11.5 hours, and the subsequent treatments are carried out in the same manner as described in Example 1. The obtained crude crystal is recrystallized from ethanol to obtain 4.3 g of intended 7-{5-[4-o,m-dimethylphenylpiperazinyl-(1)]-n-heptyl}-theophylline.

Meltint Point: 115°-117° C.

Elementary Analysis Values as C₂₄ H₃₄ O₂ N₆ : Calculated: C=65.71%, H=7.38%, N=19.16%. Found: C=65.42%, H=7.92%, N=19.31%.

EXAMPLE 4 Synthesis of 7-{7-[(3-methyl-4-m-methylphenyl)-piperazinyl-(1)]-n-heptyl}-theophylline hydrochloride

In toluene, 7.8 g of 7-(7-bromo-n-heptyl)theophylline, 3.8 g of N-(m-methylphenyl)-2-methyl-N-piperazine and 4.0 g of triethylamine are stirred under reflux for 11 hours. The subsequent treatments are carried out in the same manner as described in Example 1 to obtain 10 g of a crude crystal. The obtained crude crystal is purified by silica gel chromatography and converted to a hydrochloride according to customary procedures to obtain 5.3 g of intended 7-{7-[3-methyl(4-m-methylphenyl)piperazinyl-(1)-n-heptyl}-theophylline hydrochloride.

Melting point: 222°-265° C.

Elementary Analysis Values as C₂₆ H₃₉ O₂ N₆ Cl₂.1/2H₂ O Calculated: C=57.02%, H=7.38%, N=15.35%. Found: C=57.00%, H=7.88%, N=15.20%.

EXAMPLES 5 THROUGH 95

Compounds shown in Table 3 are prepared according to the method described in Example 1.

                                      TABLE 5                                      __________________________________________________________________________      ##STR27##                                                                                                                     Elementary Analysis                                                            Values                                                                         (upper values:                                           Recrystal-                                                                            Melting        calculated values,             Example                   lization                                                                              Point Molecular                                                                               lower values: found                                                            values)                        No.  n  X R   Z           Solvent                                                                               (°C.)                                                                         Formula  C (%)                                                                               H (%)                                                                               N(%)                 __________________________________________________________________________     5    2  N H                                                                                   ##STR28##  ethanol                                                                               228-234 (decompo- sition)                                                            C.sub.19 H.sub.24 O.sub.2 N.sub.6.                                             HCl      51.70 51.53                                                                         9.45 9.16                                                                           19.04 18.70          6    3  N H                                                                                   ##STR29##  methanol                                                                              143-145                                                                              C.sub.20 H.sub.26 O.sub.2 N.sub.6                                                       62.79 62.66                                                                         6.87 6.90                                                                           21.98 22.01          7    4  N H                                                                                   ##STR30##  ethanol                                                                               114-115                                                                              C.sub.21 H.sub.28 O.sub.2 N.sub.6                                                       63.60 63.61                                                                         7.13 7.25                                                                           21.20 21.34          8    5  N H                                                                                   ##STR31##  ethanol/ isopropyl ether                                                              112-113                                                                              C.sub.22 H.sub.30 O.sub.2 N.sub.6                                                       64.35 64.44                                                                         7.38 7.49                                                                           20.47 20.43          9    6  N H                                                                                   ##STR32##  ethanol/ isopropyl ether                                                              200-203 (decompo- sition)                                                            C.sub.23 H.sub.32 O.sub.2 N.sub.6.                                             HCl      55.52 55.26                                                                         6.90 6.71                                                                           16.90 16.59          10   2  N H                                                                                   ##STR33##  ethanol                                                                               149-150                                                                              C.sub.20 H.sub.20 O.sub.2 N.sub.6                                                       62.80 62.52                                                                         6.85 6.85                                                                           21.98 21.81          11   3  N H                                                                                   ##STR34##  ethanol                                                                               114-116                                                                              C.sub.21 H.sub.28 O.sub.2 N.sub.6                                                       63.60 63.26                                                                         7.13 7.21                                                                           21.20 20.75          12   5  N H                                                                                   ##STR35##  ethanol/ isopropyl ether                                                              113-114                                                                              C.sub.22 H.sub.32 O.sub.2 N.sub.6                                                       65.05 65.08                                                                         7.61 7.80                                                                           19.80 19.75          13   2  N H                                                                                   ##STR36##  ethanol                                                                               121-122                                                                              C.sub.20 H.sub.26 O.sub.2 N.sub.6                                                       62.80 62.98                                                                         6.85 6.83                                                                           21.98 21.97          14   4  N H                                                                                   ##STR37##  ethanol                                                                               237-239 (decom- position)                                                            C.sub.22 H.sub.30 O.sub.2 N.sub.6.                                             HCl      54.66 54.57                                                                         6.67 6.69                                                                           17.39 17.47          15   5  N H                                                                                   ##STR38##  ethanol                                                                               239-241 (decom- position)                                                            C.sub.23 H.sub.32 O.sub.2 N.sub.6.                                             HCl      55.30 55.32                                                                         6.87 6.90                                                                           16.83 16.98          16   6  N H                                                                                   ##STR39##  ethanol                                                                               224-226 (decom- position)                                                            C.sub.24 H.sub.34 O.sub.2 N.sub.6.                                             HCl      56.35 56.05                                                                         7.09 7.10                                                                           16.43 16.42          17   2  N H                                                                                   ##STR40##  ethanol/ isopropyl ether                                                              103-106                                                                              C.sub.21 H.sub.28 O.sub.2 N.sub.6                                                       63.61 63.64                                                                         7.12 7.03                                                                           21.20 21.05          18   3  N H                                                                                   ##STR41##  ethanol                                                                               116-118                                                                              C.sub.22 H.sub.30 O.sub.2 N.sub.6                                                       64.35 64.31                                                                         7.38 7.48                                                                           20.47 20.52          19   4  N H                                                                                   ##STR42##  ethanol                                                                               275-276 (decom- position)                                                            C.sub.23 H.sub.32 N.sub.6 O.sub.2.H                                            Cl       59.92 59.54                                                                         7.21 7.26                                                                           18.23 18.05          20   5  N H                                                                                   ##STR43##  ethanol                                                                               136-138                                                                              C.sub.24 H.sub.34 O.sub.2 N.sub.6                                                       65.71 66.00                                                                         7.83 7.94                                                                           19.16 19.13          21   6  N H                                                                                   ##STR44##  ethanol/ isopropyl ether                                                              167-170 (decom- position)                                                            C.sub.25 H.sub.30 O.sub.2 N.sub.6.                                             HCl      57.14 56.75                                                                         7.30 7.50                                                                           15.99 16.44          22   2  N H                                                                                   ##STR45##  ethanol                                                                               151-152                                                                              C.sub.21 H.sub.28 O.sub.2 N.sub.6                                                       63.61 63.93                                                                         7.12 7.17                                                                           21.20 21.26          23   3  N H                                                                                   ##STR46##  ethanol                                                                               153-155                                                                              C.sub.22 H.sub.30 O.sub.2 N.sub.6                                                       64.36 64.08                                                                         7.38 7.46                                                                           20.48 20.10          24   4  N H                                                                                   ##STR47##  ethanol                                                                               114-116                                                                              C.sub.23 H.sub.32 O.sub.2 N.sub.6                                                        65.05 64.63                                                                        7.61 7.53                                                                           19.80 19.79          25   5  N H                                                                                   ##STR48##  ethanol                                                                               115-117                                                                              C.sub.24 H.sub.34 O.sub.2 N.sub.6                                                       65.71 65.42                                                                         7.38 7.97                                                                           19.16 19.31          26   2  N H                                                                                   ##STR49##  ethanol                                                                               140-141                                                                              C.sub.21 H.sub.28 O.sub.2 N.sub.6                                                       63.61 63.46                                                                         7.12 6.96                                                                           21.20 21.12          27   3  N H                                                                                   ##STR50##  ethanol                                                                               128-129                                                                              C.sub.22 H.sub.30 O.sub.2 N.sub.6                                                       64.36 63.71                                                                         7.37 7.43                                                                           20.47 20.34          28   4  N H                                                                                   ##STR51##  ethanol                                                                               251-252 (decom- position)                                                            C.sub.23 H.sub.34 O.sub.2 N.sub.6.                                             Cl       59.92 59.99                                                                         7.21 7.33                                                                           18.23 18.33          29   5  N H                                                                                   ##STR52##  ethanol/ isopropyl ether                                                               80-83                                                                               C.sub.24 H.sub.34 O.sub.2 N.sub.6.                                             1/2H.sub.2 O                                                                            64.39 64.63                                                                         7.90 7.92                                                                           18.78 19.26          30   2  N H                                                                                   ##STR53##  methyl cellosolve                                                                     272-273 (decom- position)                                                            C.sub.20 H.sub.20 O.sub.3 N.sub.6.                                             HCl      50.95 50.76                                                                         6.00 5.68                                                                           17.83 17.52          31   3  N H                                                                                   ##STR54##  methanol                                                                              240-243 (decom- position)                                                            C.sub.21 H.sub.28 O.sub.3 N.sub.6.                                             HCl      51.95 51.76                                                                         6.24 6.15                                                                           17.31 16.98          32   4  N H                                                                                   ##STR55##  ethanol                                                                               117-118                                                                              C.sub.22 H.sub.30 O.sub.3 N.sub.6                                                       61.94 62.10                                                                         7.10 7.21                                                                           19.71 19.86          33   5  N H                                                                                   ##STR56##  ethanol                                                                               120-121                                                                              C.sub.23 H.sub. 32 O.sub.3                                                     N.sub.6.H.sub.2 O                                                                       60.23 60.50                                                                         7.49 7.20                                                                           18.33 18.37          34   6  N H                                                                                   ##STR57##  ethanol/ isopropyl ether                                                              213-215 (decom- position)                                                            C.sub.24 H.sub.34 O.sub.3 N.sub.6.                                             HCl      54.63 54.61                                                                         6.89 6.58                                                                           15.93 15.49          35   2  N H                                                                                   ##STR58##  methyl cellosolve                                                                     170-171                                                                              C.sub.20 H.sub.26 O.sub.3 N.sub.6                                                       60.28 60.58                                                                         6.58 6.63                                                                           21.09 21.14          36   3  N H                                                                                   ##STR59##  methyl cellosolve                                                                     161-163                                                                              C.sub.21 H.sub.28 O.sub.3 N.sub.6                                                       61.13 61.12                                                                         6.85 6.85                                                                           20.38 20.58          37   4  N H                                                                                   ##STR60##  methanol                                                                              211-212 (decom- position)                                                            C.sub.22 H.sub.30 O.sub.3 N.sub.6.                                             Cl       57.07 56.99                                                                         6.75 6.64                                                                           18.15 18.05          38   5  N H                                                                                   ##STR61##  ethanol                                                                               120-121                                                                              C.sub.23 H.sub.32 O.sub.3 N.sub.6.                                             .sub.2 O 60.23 60.50                                                                         7.49 7.20                                                                           18.33 18.37          39   6  N H                                                                                   ##STR62##  ethanol                                                                               208-210 (decom- position)                                                            C.sub.24 H.sub.34 O.sub.3 N.sub.6                                              HCl      54.64 54.51                                                                         6.88 6.91                                                                           15.93 15.99          40   2  N H                                                                                   ##STR63##  ethanol                                                                               155-156                                                                              C.sub.20 H.sub.26 O.sub.3 N.sub.6                                                       60.28 60.12                                                                         6.58 6.59                                                                           21.09 21.05          41   3  N H                                                                                   ##STR64##  methyl cellosolve                                                                     165-167                                                                              C.sub.21 H.sub.28 O.sub.3 N.sub.6                                                       61.13 61.18                                                                         6.85 6.92                                                                           20.38 20.26          42   4  N H                                                                                   ##STR65##  ethanol                                                                               115-116                                                                              C.sub.22 H.sub.30 O.sub.3 N.sub.6                                                       61.94 61.77                                                                         7.10 19.71 19.46          43   5  N H                                                                                   ##STR66##  ethanol                                                                               127-129                                                                              C.sub.23 H.sub.32 O.sub.3 N.sub.6                                                       62.69 62.36                                                                         7.33 7.33                                                                           19.08 19.41          44   4  N H                                                                                   ##STR67##  ethanol/ methyl cellosolve                                                            161-162                                                                              C.sub.19 H.sub.23 O.sub.2 N.sub.6                                              Cl       56.64 56.79                                                                         5.77 5.60                                                                           20.86 20.93          45   3  N H                                                                                   ##STR68##  ethanol                                                                               121-122                                                                              C.sub.20 H.sub.25 O.sub.2 N.sub.6                                              Cl       57.61 57.64                                                                         6.06 5.96                                                                           20.16 20.23          46   2  N H                                                                                   ##STR69##  acetone                                                                               117-119                                                                              C.sub.22 H.sub.29 O.sub.2 N.sub.6                                              Cl       59.37 59.53                                                                         6.58 6.80                                                                           18.89 19.11          47   2  N H                                                                                   ##STR70##  methyl cellosolve                                                                     134-136                                                                              C.sub.19 H.sub.23 O.sub.2 N.sub.6                                              Cl       56.63 56.86                                                                         5.77 5.93                                                                            20.86 20.63         48   3  N H                                                                                   ##STR71##  ethanol                                                                               109-111                                                                              C.sub.20 H.sub.25 O.sub.2 N.sub.6                                              Cl       57.61 57.55                                                                         6.06 6.35                                                                           20.16 19.00          49   4  N H                                                                                   ##STR72##  isopropanol/ isopropyl ether                                                           96-98                                                                               C.sub.21 H.sub.27 O.sub.2 N.sub.6                                              Cl       58.52 58.82                                                                         6.33 6.41                                                                           19.51 19.26          50   5  N H                                                                                   ##STR73##  ethanol/ methanol                                                                     151-154                                                                              C.sub.22 H.sub.31 O.sub.2 N.sub.6                                              Cl.sub.3.1/2 H.sub.2 O                                                                  50.04 50.02                                                                         6.13 6.17                                                                           16.23 15.93          51   2  N H                                                                                   ##STR74##  methyl cellosolve                                                                     167-169                                                                              C.sub.19 H.sub.23 O.sub.2 N.sub.6                                              Cl       56.63 56.66                                                                         5.77 5.81                                                                           20.86 20.91          52   3  N H                                                                                   ##STR75##  methyl cellosolve                                                                     241-244 (decom- position)                                                            C.sub.20 H.sub.25 O.sub.2 N.sub.6                                              Cl. 2HCl 49.03 48.66                                                                         5.57 5.20                                                                           17.16 16.84          53   4  N H                                                                                   ##STR76##  ethanol                                                                               107-109                                                                              C.sub.21 H.sub.27 O.sub.2 N.sub.6                                              Cl       58.52 58.77                                                                         6.33 6.38                                                                           19.50 19.44          54   5  N H                                                                                   ##STR77##  isopropanol/ ether                                                                    127-130                                                                              C.sub.22 H.sub.29 O.sub.2 N.sub.6                                              Cl. 2HCl 51.01 50.49                                                                         6.05 6.20                                                                           16.23 16.02          55   6  N H                                                                                   ##STR78##  methanol                                                                              110-111                                                                              C.sub.23 H.sub.31 O.sub.2 N.sub.6                                              Cl       60.17 60.20                                                                         6.82 6.96                                                                           18.31 18.68          56   2  N H                                                                                   ##STR79##  methyl cellosolve                                                                     146-147                                                                              C.sub.19 H.sub.22 O.sub.2 N.sub.6                                              Cl.sub.2 52.18 52.23                                                                         5.07 4.95                                                                           19.22 19.39          57   3  N H                                                                                   ##STR80##  methyl cellosolve                                                                     124-126                                                                              C.sub.20 H.sub.24 O.sub.2 N.sub.6                                              Cl.sub.2 53.21 53.50                                                                         5.37 5.32                                                                           18.62 18.52          58   4  N H                                                                                   ##STR81##  methanol                                                                              130-132                                                                              C.sub.21 H.sub.26 O.sub.2 N.sub.6                                              Cl.sub.2 54.19 54.44                                                                         5.64 5.73                                                                           18.06 18.21          59   3  N H                                                                                   ##STR82##  methanol                                                                              128-129                                                                              C.sub.20 H.sub.25 O.sub.2 N.sub.6                                              F        59.97 59.94                                                                         6.30 6.31                                                                           20.99 21.12          60   4  N H                                                                                   ##STR83##  methanol                                                                              223-226 (decom- position)                                                            C.sub.21 H.sub.27 O.sub.2 N.sub.6                                              F. 2HCl  51.74 51.65                                                                         6.00 5.84                                                                           17.25 16.94          61   5  N H                                                                                   ##STR84##  ethanol/ methanol                                                                     140-141                                                                              C.sub.22 H.sub.29 O.sub.2 N.sub.6                                              F        61.65 61.32                                                                         6.83 6.77                                                                           19.61 19.67          62   3  N H                                                                                   ##STR85##  methanol                                                                              115-116                                                                              C.sub.21 H.sub.25 O.sub.2 N.sub.6                                              F.sub.3  55.98 56.46                                                                         5.60 5.71                                                                           18.66 19.26          63   4  N H                                                                                   ##STR86##  ethanol/ isopropyl ether                                                              215-218                                                                              C.sub.22 H.sub.26 O.sub.2 N.sub.6                                              F.sub.3. 2HCl                                                                           49.16 49.25                                                                         5.26 5.42                                                                           15.64 16.21          64   5  N H                                                                                   ##STR87##  ethanol/ isopropyl ether                                                              114-115                                                                              C.sub.23 H.sub.29 O.sub.2 N.sub.6                                              F.sub.3  57.72 57.55                                                                         6.12 6.13                                                                           17.56 17.71          65   2  N H                                                                                   ##STR88##  methanol                                                                              153-155                                                                              C.sub.18 H.sub.23 O.sub.2 N.sub.7                                                       58.51 58.48                                                                         6.29 6.38                                                                           26.54 26.22          66   3  N H                                                                                   ##STR89##  ethanol                                                                               139-140                                                                              C.sub.19 H.sub.25 O.sub.2 N.sub.7                                                       59.50  59.52                                                                        6.58 6.65                                                                           25.57 25.80          67   4  N H                                                                                   ##STR90##  ethanol                                                                               120-121                                                                              C.sub.20 H.sub.27 O.sub.2 N.sub.7                                                       60.42 60.14                                                                         6.86 6.90                                                                           24.67 24.40          68   5  N H                                                                                   ##STR91##  ethanol/ isopropyl ether                                                              102-104                                                                              C.sub.21 H.sub.29 O.sub.2 N.sub.7                                                       61.28 61.26                                                                         7.12 7.11                                                                           23.83 23.66          69   6  N H                                                                                   ##STR92##  ethanol                                                                                96-97                                                                               C.sub.22 H.sub.31 O.sub.2 N.sub.7                                                       62.08 62.01                                                                         7.36 7.46                                                                           23.04 23.35          70   3  N H                                                                                   ##STR93##  methyl cellosolve                                                                     252-254                                                                              C.sub.27 H.sub.32 O.sub.2 N.sub.6.                                             HCl      59.44 59.28                                                                         6.29 6.42                                                                           15.41 15.59          71   4  N H                                                                                   ##STR94##  ethanol/ methanol                                                                     238-240                                                                              C.sub.23 H.sub.34 O.sub. 2                                                     N.sub.6. 2HCl                                                                           60.09 59.14                                                                         6.50 6.48                                                                           15.02 14.93          72   5  N H                                                                                   ##STR95##  methyl cellosolve                                                                     115-117 (decom- position)                                                            C.sub.29 H.sub.36 O.sub.2 N.sub.6                                                       69.56 69.87                                                                         7.26 7.39                                                                           16.79 16.70          73   6  N H                                                                                   ##STR96##  ethanol                                                                               212-214                                                                              C.sub.30 H.sub.38 O.sub.2 N.sub.6.                                             HCl      61.30 61.27                                                                         6.87 7.04                                                                           14.30 14.51          74   2  N H                                                                                   ##STR97##  methyl cellosolve                                                                     250-252                                                                              C.sub.26 H.sub.29 O.sub.2 N.sub.6                                              Cl. 2HCl 55.16 55.19                                                                         5.53 5.38                                                                           14.85 14.87          75   3  N H                                                                                   ##STR98##  methyl cellosolve                                                                     222 (decom- position)                                                                C.sub.27 H.sub.31 O.sub. 2 N.sub.6                                             Cl. 2HCl.H.sub.2 O                                                                      54.22 53.64                                                                         5.91 5.92                                                                           14.06 14.09          76   4  N H                                                                                   ##STR99##  methanol                                                                              208-210                                                                              C.sub.28 H.sub.33 O.sub.2 N.sub.6                                              Cl. 2HCl 56.61 55.97                                                                         5.95 6.04                                                                           14.15 13.92          77   5  N H                                                                                   ##STR100## ethanol/ isopropyl ether                                                              117-119                                                                              C.sub.29 H.sub.35 O.sub.2 N.sub.6                                              Cl       65.08 65.23                                                                         6.60 6.64                                                                           15.70 16.02          78   6  N H                                                                                   ##STR101## ethanol                                                                               201-203                                                                              C.sub.30 H.sub.37 O.sub.2 N.sub.6                                              Cl. 2HCl.1/2H.sub.2 O                                                                   57.09 57.00                                                                         6.40 6.54                                                                           13.32 13.90          79   2  N CH.sub.3                                                                            ##STR102## ethanol                                                                               128-130                                                                              C.sub.20 H.sub.26 O.sub.2 N.sub.6                                                       62.80 62.73                                                                          6.85 6.87                                                                          21.98 21.91          80   4  N CH.sub.3                                                                            ##STR103## isopropanol                                                                            99-100                                                                              C.sub.22 H.sub.30 O.sub.2 N.sub.6                                                       64.36 64.51                                                                         7.37 7.47                                                                           20.47 20.87          81   5  N CH.sub.3                                                                            ##STR104## acetone/ isopropyl ether                                                              111-113                                                                              C.sub.21 H.sub.28 O.sub.2 N.sub.6                                                       63.28 63.74                                                                         7.09 7.12                                                                           21.09 21.35          82   2  N CH.sub.3                                                                            ##STR105## ethanol                                                                               117-118                                                                              C.sub.21 H.sub.28 N.sub.6 O.sub.3                                                       61.14 61.00                                                                         6.84 6.94                                                                           20.38 20.23          83   5  N CH.sub.3                                                                            ##STR106## isopropanol                                                                            85-87                                                                               C.sub.24 H.sub.31 O.sub.3 N.sub.6                                                       63.82 63.56                                                                         6.93 7.69                                                                           18.61 18.63          84   2  C H                                                                                   ##STR107## methanol                                                                              155-156                                                                              C.sub.20 H.sub.25 O.sub.2 N.sub.5                                                       65.36 65.69                                                                         6.87 6.80                                                                           19.06 19.17          85   3  C H                                                                                   ##STR108## methyl cellosolve                                                                     157-159                                                                              C.sub.21 H.sub.27 O.sub.2 N.sub.5                                                       66.10 66.05                                                                         7.15 7.16                                                                           18.36 18.55          86   4  C H                                                                                   ##STR109## ethanol                                                                               117-118                                                                              C.sub.22 H.sub.29 O.sub.2 N.sub.5                                                       66.80 67.01                                                                         7.40 7.51                                                                           17.71 17.70          87   7  N CH.sub.3                                                                            ##STR110## ethanol/ isopropyl ether                                                              200-204                                                                              C.sub.25 H.sub.35 O.sub.2 N.sub.6                                              Cl. HCl.H.sub.2 O                                                                       55.44 55.36                                                                         7.09 6.88                                                                           15.52 15.92          88   7  N H                                                                                   ##STR111## hydrous ethanol                                                                       239-241                                                                              C.sub.26 H.sub.37 O.sub.2 N.sub.6.                                             HCl.1/2H.sub.2 O                                                                        57.02 57.46                                                                         7.38 7.45                                                                           15.35 15.77          89   8  N H                                                                                   ##STR112## hydrous ethanol                                                                       181-183                                                                              C.sub.27 H.sub.40 N.sub.6 O.sub.2.                                             HCl      58.79 58.71                                                                         7.68 7.58                                                                            15.24 15.22         90   5  N H                                                                                   ##STR113## ethanol/ isopropyl ether                                                              112-114                                                                              C.sub.22 H.sub.26 O.sub.2 N.sub.6.                                             Cl       55.11 55.09                                                                         5.90 5.93                                                                           17.53 17.31          91   7  N H                                                                                   ##STR114## hydrous methanol                                                                      223-226 (decom- position)                                                            C.sub.25 H.sub.35 O.sub.2 N.sub.6                                              Cl. 2HCl 53.90 53.49                                                                         6.17 6.60                                                                           15.09 15.50          92   10 N H                                                                                   ##STR115## ethanol                                                                               207-209 (decom- position)                                                            C.sub.28 H.sub.41 O.sub.3 N.sub.6.                                             HCl      57.71 57.76                                                                         7.45 7.91                                                                           14.43 14.11          93   10 N H                                                                                   ##STR116## ethanol                                                                               211-213 (decom- position)                                                            C.sub.28 H.sub.41 O.sub.2 N.sub.6                                              Cl. HCl  59.45 59.31                                                                         7.50 14.80 14.69          94   10 N CH.sub.3                                                                            ##STR117## methanol/ isopropyl ether                                                             211-214 (decom- position)                                                            C.sub.29 H.sub.46 O.sub.2 N.sub.6.                                             HCl.2H.sub.2 O                                                                          56.38 56.12                                                                         8.17 7.76                                                                           13.60 13.46          95   10 N H                                                                                   ##STR118## methanol/ isopropyl ether                                                             187-190 (decom- position)                                                            C.sub.29 H.sub.44 O.sub.2 N.sub.6.                                             HCl      59.87 59.42                                                                         7.99 7.96                                                                           14.45 14.09          __________________________________________________________________________

EXAMPLE 96 Synthesis of 1-{4-[4-o,m-dimethylphenylpiperazinyl-(1)-n-butyl}-theobromine

In toluene, 9.5 g of 1-(4-bromo-n-butyl)theobromine, 3.8 g of o,m-dimethylphenylpiperazine and 4.0 g of triethylamine are stirred under reflux for 13 hours. Triethylamine hydrochloride is removed by filtration and the filtrate is extracted with dilute hydrochloric acid. The extract is made alkaline by dilute sodium hydroxide and is then extracted with chloroform. The chloroform layer is washed with water and dried with anhydrous potassium carbonate. The solvent is removed by distillation and the residual crude crystal is recrystallized from methyl cellosolve to obtain 3.7 g of intended 1-{4-[4-o,m-dimethylphenylpiperazinyl-(1)]-n-butyl}-theobromine (the yield being 43.64%).

Melting Point: 134°-135° C.

Elementary Analysis Values as C₂₃ H₃₂ O₂ N₆ : Calculated: C=65.05%, H=7.61%, N=19.80%. Found: C=65.11%, H=7.72%, N=19.46%.

EXAMPLE 97 Synthesis of 1-{5-[4-benzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine hydrochloride

In toluene, 7.9 g of 1-(5-bromo-n-pentyl)theobromine, 5.0 g of N-benzyhydrylpiperazine and 4 g of triethylamine are stirred under reflux for 30 hours. The subsequent treatments are carried out in the same manner as described in Example 96. The obtained crude crystal is converted to a hydrochloride according to customary procedures to obtain 4.7 g of intended 1-}5-[4-benzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine hydrochloride (the yield being 40.9%).

Melting Point: 262°-264° C. (decomposition).

Elementary Analysis Values as C₂₉ H₃₆ O₂ N₆.2HCl: Calculated: C=60.93%, H=6.71%, N=14.71%. Found: C=60.57%, H=7.15%, N=14.65%.

EXAMPLE 98 Synthesis of 1-{7-[4-o-methoxyphenylpiperazinyl-(1)]-n-heptyl}-theobromine

In toluene, 7.5 g of 1-(7-bromo-n-heptyl)theobromine, 3.8 g of N-o-methoxyphenylpiperazine and 4.0 g of triethylamine are stirred under reflux for 11.5 hours, and the subsequent treatments are carried out in the same manner as described in Example 96. The obtained crude crystal is purified by silica gel chromatography to obtain 4.6 g of intended 1-7-[4-o-methoxyphenylpiperazinyl(1)-n-heptyl-theobromine (the yield being 49.1%).

Melting Point: 97°-98° C.

Elementary Analysis Values as C₂₅ H₃₆ O₃ N₆ : Caculated: C=64.08%, H=7.74%, N=17.94%. Found: C=63.90%, H=7.67%, N=18.01%.

EXAMPLES 99 THROUGH 148

Compounds shown in Table 6 are prepared according to the method described in Example 96.

                                      TABLE 6                                      __________________________________________________________________________      ##STR119##                                                                                                                   Elementary Analysis                                                            Values                          Ex-                    Recrystal-                                                                            Melting          (upper values: calculated                                                      values,                         ample                  lization                                                                              Point                                                                               Molecular   lower values: found                                                            values)                         No. n  R   Z           Solvent                                                                               (°C.)                                                                        Formula     C (%)                                                                               H (%) N                    __________________________________________________________________________                                                               (%)                   99 6  H                                                                                   ##STR120## ethanol                                                                               197-198 (decom- position)                                                           C.sub.24 H.sub.34 N.sub.6 O.sub.2.2HCl.                                        2H.sub.2 O  52.65 52.64                                                                         7.01 7.10                                                                            15.35 15.28          100 2  H                                                                                   ##STR121## ethanol                                                                               251 (decom- position)                                                               C.sub.20 H.sub.26 O.sub.2 N.sub.6.2HCl                                                     52.75 52.41                                                                         6.21 6.11                                                                            18.46 18.31          101 5  H                                                                                   ##STR122## ethanol                                                                               133-135                                                                             C.sub.23 H.sub.32 O.sub.2 N.sub.6                                                          65.05 65.03                                                                         7.61 7.62                                                                            19.80 19.82          102 6  H                                                                                   ##STR123## ethanol                                                                               206-208 (decom- position)                                                           C.sub.24 H.sub.34 O.sub.2 N.sub.6.2HCl.                                        2H.sub.2 O  52.65 53.10                                                                         7.01 6.91                                                                            15.35 15.44          103 2  H                                                                                   ##STR124## ethanol                                                                               151-153                                                                             C.sub.21 H.sub.28 O.sub.2 N.sub.6                                                          63.60 63.60                                                                         7.13 7.05                                                                            21.20 21.28          104 3  H                                                                                   ##STR125## ethanol                                                                               154-156                                                                             C.sub.22 H.sub.30 O.sub.2 N.sub.6                                                          64.36 64.13                                                                         7.37 7.49                                                                            20.47 20.32          105 4  H                                                                                   ##STR126## ethanol                                                                               124-126                                                                             C.sub.23 H.sub.32 O.sub.2 N.sub.6                                                          65.05 65.03                                                                         7.61 7.61                                                                            19.80 19.82          106 5  H                                                                                   ##STR127## ethanol                                                                               121-123                                                                             C.sub.24 H.sub.34 O.sub.2 N.sub.6                                                          65.71 65.68                                                                         7.38 7.73                                                                            19.16 19.36          107 2  H                                                                                   ##STR128## ethanol                                                                               161-162                                                                             C.sub.21 H.sub.28 O.sub.2 N.sub.6                                                          63.60 63.67                                                                         7.13 7.07                                                                            21.20 21.16          108 3  H                                                                                   ##STR129## ethanol                                                                               124-126                                                                             C.sub.23 H.sub.30 O.sub.2 N.sub.6                                                          64.36 63.65                                                                         7.37 7.20                                                                            20.47 20.32          109 4  H                                                                                   ##STR130## methyl cellosolve                                                                     134-135                                                                             C.sub.23 H.sub.32 O.sub.2 N.sub.6                                                          65.05  65.11                                                                        7.61 7.72                                                                            19.80 19.46          110 5  H                                                                                   ##STR131## ethanol/ isopropyl ether                                                              118-120                                                                             C.sub.24 H.sub.34 O.sub.2 N.sub.6                                                          65.71 65.65                                                                         7.38 7.95                                                                            19.16 18.94          111 6  H                                                                                   ##STR132## isopropanol/ isopropyl ether                                                           91-93                                                                              C.sub.25 H.sub.36 O.sub.2 N.sub.6                                                          66.34 65.84                                                                         8.02 8.31                                                                            18.57 18.50          112 2  H                                                                                   ##STR133## ethanol                                                                               139-141                                                                             C.sub.21 H.sub.28 O.sub.2 N.sub.6                                                          63.61 63.73                                                                         7.12 7.30                                                                            21.20 21.21          113 3  H                                                                                   ##STR134## ethanol                                                                               137-139                                                                             C.sub.22 H.sub.30 O.sub.2 N.sub.6                                                          64.36 64.19                                                                         7.37 7.44                                                                            20.47 20.36          114 4  H                                                                                   ##STR135## ethanol                                                                               148-150                                                                             C.sub.23 H.sub.32 O.sub.2 N.sub.6                                                          65.05 64.44                                                                         7.61 7.52                                                                            19.80 19.70          115 5  H                                                                                   ##STR136## isopro- panol                                                                          99-101                                                                             C.sub.24 H.sub.34 O.sub.2 N.sub.6                                                          65.71 65.33                                                                         7.38 7.79                                                                            19.16 19.12          116 6  H                                                                                   ##STR137## ethanol/ isopropyl ether                                                               89-90                                                                              C.sub.25 H.sub.36 O.sub.2 N.sub.6                                                          66.33 66.26                                                                         8.03 8.21                                                                            18.57 18.24          117 5  H                                                                                   ##STR138## ethanol                                                                               165-166 (decom- position)                                                           C.sub.23 H.sub.32 O.sub.3 N.sub.6.HCl                                                      57.91 57.81                                                                         6.97 7.19                                                                            17.62 17.21          118 6  H                                                                                   ##STR139## ethanol/ methanol                                                                      79-81                                                                              C.sub.24 H.sub.34 O.sub.3 N.sub.6                                                          63.40 63.35                                                                         7.55 7.70                                                                            18.49 18.69          119 2  H                                                                                   ##STR140## ethanol                                                                               122-124                                                                             C.sub.19 H.sub.23 O.sub.2 N.sub.6                                                          56.63 56.67                                                                         5.77 5.67                                                                            20.86 21.19          120 4  H                                                                                   ##STR141## isopropanol/ isopropyl ether                                                          111-113                                                                             C.sub.21 H.sub.27 O.sub.2 N.sub.6                                              Cl.1/22H.sub.2 O                                                                           57.33 57.53                                                                         6.65 6.29                                                                            19.10 19.14          121 6  H                                                                                   ##STR142## isopropanol/ methanol                                                                 106-107                                                                             C.sub.23 H.sub.31 O.sub.2 N.sub.6                                                          60.17 60.21                                                                         6.82 6.97                                                                            18.31 18.63          122 2  CH.sub.3                                                                            ##STR143## methyl cellosolve                                                                     176-178                                                                             C.sub.20 H.sub.26 O.sub.2 N.sub.6                                                          62.79 63.19                                                                         6.87 6.89                                                                            21.98 22.03          123 3  CH.sub.3                                                                            ##STR144## ethanol                                                                               126-128                                                                             C.sub.21 H.sub.28 O.sub.2 N.sub.6                                                          63.61 63.56                                                                         7.12 7.28                                                                            21.20 21.54          124 4  CH.sub.3                                                                            ##STR145## ethanol                                                                               120-122                                                                             C.sub.22 H.sub.30 O.sub.2 N.sub.6                                                          64.35 64.81                                                                         7.38 7.47                                                                            20.47 20.37          125 5  CH.sub.3                                                                            ##STR146## ethanol/ isopropyl ether                                                              102-104                                                                             C.sub.23 H.sub.32 O.sub.2 N.sub.6                                                          65.07 65.10                                                                         7.60 7.77                                                                            19.80 19.82          126 6  CH.sub.3                                                                            ##STR147## ethanol                                                                               101-103                                                                             C.sub.24 H.sub.34 O.sub.2 N.sub.6                                                          65.71 65.64                                                                         7.38 7.95                                                                            19.16 19.19          127 2  CH.sub.3                                                                            ##STR148## isopropanol                                                                           118-119                                                                             C.sub.21 H.sub.25 O.sub.3 N.sub.6.1/22H                                        .sub.2 O    60.27 60.73                                                                         6.28 6.81                                                                            20.09 20.15          128 3  CH.sub.3                                                                            ##STR149## methanol                                                                              142-143                                                                             C.sub.22 H.sub.30 O.sub.3 N.sub.6                                                          61.95 61.95                                                                         7.09 7.13                                                                            19.71 19.91          129 4  CH.sub.3                                                                            ##STR150## ethanol                                                                               108-110                                                                             C.sub.23 H.sub. 32 O.sub.3 N.sub.6                                                         62.70 62.84                                                                         7.32 7.39                                                                            19.08 19.24          130 3  H                                                                                   ##STR151## methyl cellosolve                                                                     162-163                                                                             C.sub.20 H.sub.24 O.sub.2 N.sub.6                                              Cl.sub.2    53.21 53.11                                                                         5.37 5.41                                                                            18.62 18.62          131 4  H                                                                                   ##STR152## methyl cellosolve                                                                     140-142                                                                             C.sub.21 H.sub.26 O.sub.2 N.sub.6                                              Cl.sub.2    54.19 54.24                                                                         5.64 5.71                                                                            18.06 17.91          132 5  H                                                                                   ##STR153## methyl cellosolve                                                                     132-134                                                                             C.sub.22 H.sub.28 O.sub.2 N.sub.6                                              Cl.sub.2    55.11 55.03                                                                         5.90 5.86                                                                            17.53 17.65          133 6  H                                                                                   ##STR154## ethanol                                                                               144-145                                                                             C.sub.23 H.sub.30 O.sub.2 N.sub.6                                              Cl.sub.2    55.57 56.04                                                                         6.14 6.32                                                                            17.03 17.09          134 2  H                                                                                   ##STR155## ethanol                                                                               175-176                                                                             C.sub.26 H.sub.30 O.sub.2 N                                                                68.10 68.20                                                                         6.59 6.57                                                                            18.33 18.50          135 3  H                                                                                   ##STR156## ethanol                                                                               150-151                                                                             C.sub.27 H.sub.32 O.sub.2 N.sub.6                                                          68.62 68.66                                                                         6.83 6.87                                                                            17.79 17.85          136 4  H                                                                                   ##STR157## methyl cellosolve                                                                     163-165                                                                             C.sub.28 H.sub.34 O.sub.2 N.sub.6                                                          69.10 68.96                                                                         7.06 7.00                                                                            17.27 17.22          137 5  H                                                                                   ##STR158## isopropanol                                                                           262-264                                                                             C.sub.29 H.sub.36 O.sub.2 N.sub.6.2HCl                                                     60.93 60.57                                                                         6.71 7.15                                                                            14.71 14.65          138 2  H                                                                                   ##STR159## methanol                                                                              228-230 (decom- position)                                                           C.sub.26 H.sub.29 O.sub.2 N.sub.6.2HCl.                                        H.sub.2 O   53.48 54.05                                                                         5.70 5.45                                                                            14.40 14.35          139 3  H                                                                                   ##STR160## methyl cellosolve                                                                     194-195 (decom- position)                                                           C.sub.27 H.sub.31 O.sub.2 N.sub.6.2HCl.                                        2H.sub.2 O  52.64 53.21                                                                         5.74 5.95                                                                            13.64 13.74          140 4  H                                                                                   ##STR161## ethanol/ isopropyl ether                                                              142-144                                                                             C.sub.28 H.sub.33 O.sub.2 N.sub.6                                                          64.53 64.76                                                                         6.40 6.52                                                                            16.13 16.16          141 5  H                                                                                   ##STR162## methanol/ ethanol                                                                      85-87                                                                              C.sub.29 H.sub.35 O.sub.2 N.sub.6                                              Cl.2HCl     57.47 56.96                                                                         6.17 6.68                                                                            13.87 13.73          142 6  H                                                                                   ##STR163## ethanol/ isopropyl ether                                                               85-88                                                                              C.sub.30 H.sub.37 O.sub.2 N.sub.6                                              Cl.2HCl     57.92 57.56                                                                         6.33 6.69                                                                             13.51 13.14         143 7  H                                                                                   ##STR164## acetone/ isopropyl ether                                                               81-83                                                                              C.sub.24 H.sub.33 O.sub.2 N.sub.6                                                          63.12 62.69                                                                         7.30 7.33                                                                            18.41 18.33          144 7  H                                                                                   ##STR165## purified by column chro- matography (silica                                            90-91                                                                              C.sub.25 H.sub.36 O.sub.2 N.sub.6                                                          66.34 66.24                                                                         8.02 8.03                                                                            18.57 18.54          145 8  H                                                                                   ##STR166## hydrous ethanol                                                                       173-177                                                                             C.sub.26 H.sub.38 N.sub.6 O.sub.3.2HCl.                                        H.sub.2 O   54.44 54.19                                                                         7.38 7.37                                                                            14.65 14.67          146 8  H                                                                                   ##STR167## hydrous ethanol                                                                       228-230                                                                             C.sub.27 H.sub.40 N.sub.6 O.sub.2.HCl                                                      62.95 62.91                                                                         8.62 8.04                                                                            16.32 16.41          147 10 H                                                                                   ##STR168## hydrous ethanol                                                                       147-150                                                                             C.sub.29 H.sub.44 N.sub.6 O.sub.2.2HCl.                                        H.sub.2 O   58.08 58.28                                                                         8.07 8.08                                                                            14.02 13.94          148 10 CH.sub.3                                                                            ##STR169## ethanol                                                                               154-157                                                                             C.sub.29 H.sub.44 N.sub.6 O.sub.3.2HCl.                                        1/2H.sub.2 O                                                                               57.44 57.32                                                                         7.81 7.92                                                                            13.86 13.84          __________________________________________________________________________ 

What is claimed is:
 1. A compound having the formula ##STR170## in which one of R₁ and R₂ is methyl and the other of R₁ and R₂ has the formula ##STR171## wherein R is hydrogen or lower alkyl; Z is pyridyl and or ##STR172## in which Y₁ and Y₂, which are the same or different, are hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen; X is C; and n is an integer of from 2 to 10; with the proviso that when R₁ is methyl, R₂ is not ##STR173## or a pharmaceutically acceptable salt thereof.
 2. A compound having the formula ##STR174## wherein R is hydrogen or lower alkyl; Z is selected from the group consisting of (a) ##STR175## in which X₁ and X₂, which are the same or different, are hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen, (b) pyridyl and (c) ##STR176## in which Y₁ and Y₂, which are the same or different, are hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen; X is C; and n is an integer of from 2 to 10; or a pharmaceutically acceptable salt thereof.
 3. A compound having the formula ##STR177## in which X₁ and X₂, which are the same or different, are hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen; and n is an integer of from 2 to 10; or a pharmaceutically acceptable salt thereof.
 4. A compound as claimed in claim 3 in which n is 4, X₁ is m-methoxy and X₂ is hydrogen.
 5. A composition as claimed in claim 3 in which n is 4, X₁ is p-chloro and X₂ is hydrogen.
 6. A pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined in claim 1, for vasodilating purposes, in combination with a pharmacologically acceptable carrier.
 7. A pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined in claim 1, for analgesic purposes, in combination with a pharmacologically acceptable carrier.
 8. A method for treating a subject suffering from blood circulatory insufficiency which comprises administering to the subject a pharmaceutical composition as defined in claim
 6. 9. A method for treating a subject suffering from a pain which comprises administering to the subject a pharmaceutical composition as defined in claim
 7. 10. A compound of the formula ##STR178## wherein R is hydrogen or lower alkyl, and Y₁ and Y₂, which are the same or different, are hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen; X is C; and n is an integer of from 2 to 10; or a pharmaceutically acceptable salt thereof.
 11. A pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined in claim 2, for vasodilating purposes, in combination with a pharmacologically acceptable carrier.
 12. A pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined in claim 2, for analgesic purposes, in combination with a pharmacologically acceptable carrier.
 13. A method for treating a subject suffering from blood circulatory insufficiency which comprises administering to the subject a pharmaceutical composition as defined in claim
 11. 14. A method for treating a subject suffering from a pain which comprises administering to the subject a pharmaceutical composition as defined in claim
 12. 